Project: Colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Having a better understanding of the regulation of chemoresistance in CRC cells would lead to new therapeutic strategies and improve outcomes for patients with mCRC. Our preliminary studies showed that ECs secrete soluble factors to conditioned medium (CM), in turn, increased cancer cell survival by activating human epidermal growth factor receptor 3 (HER3, also known as ERBB3) in RAS wildtype and mutant CRC cells. However, the EC-secreted factor(s) for HER3 activation and the mechanism(s) of activating HER3 in CRC cells are unknown. We hypothesize CRC-associated HER3 mediates the EC paracrine effects on promoting CRC cell survival independent of RAS mutations. In Aim 1, we will determine the role of HER3 in EC-induced CRC cell survival in in vitro and in vivo. In Aim 2, we will identify the EC-secreted factor(s) that activate HER3 in CRC cells. In Aim 3, we will identify the co-factors in CRC cells that couple with and activate HER3. Our long term goal of this project is to identify and validate new targets for developing potential therapeutic approaches for patients with mCRC. Studies in this proposal will help us to better understand HER3, a receptor that is not well studied compared to other HER receptors. This project will serve as the foundation of novel therapies for treating patients with mCRC utilizing HER3 antibodies/inhibitors that are already being assessed in clinical trials for various cancer types. Candidate: My long-term career goal is to be an independent investigator conducting translational research and teaching/mentoring focusing on studies that will lead to a better understanding of CRC biology and help improving clinical therapy for patients with mCRC, and potentially with other cancer types. Career Development plan: In addition to conduct research- and career development-related trainings described in the proposal, I will learn specific subjects from each committee member. (1) My mentor Dr. Lee Ellis will teach me clinical problems related to CRC and the practical aspects of developing clinical trials in collaboration with Medical Oncologists. (2) My co-mentor Dr. Sendurai Mani will teach me the mechanisms by which microenvironment affects cancer cell functions. (3) My committee member Dr. Mien-Chie Hung will teach me the effects of HER3 on cancer cell functions. Environment: The clinic- orientated environment at M.D. Anderson Cancer Center (MDACC) and my current laboratory has offered me ample opportunities to understand the complicities of cancer biology and clinical aspects of CRC. MDACC is located in the center of the Texas Medical Center (TMC), which has 54 medicine-related institutions that are all within a 5-mile radius. In addition to use resources available at MDACC, I will attend TMC-hosted research- and career development-related seminars, and use core facilities from other institutions, when necessary. My concentration on translational CRC research and enthusiasm for establishing an independently funded research laboratory in this area fit well with the mission of NCI and with the objectives of the K99/R00 award.